This study aimed to evaluate the effectiveness of a novel calcitonin-loaded calcium phosphate composite bone cement in vitro and in vivo. The novel composite bone cements were composed of NuROs injectable bone graft substitute, type I collagen, and/or salmon calcitonin. The setting time, porosity, wettability, compressive strength, compressive modulus, and crystallographic structures of cement specimens were determined. Degradation rate, calcitonin release rate, and osteoinductivity were assessed in vitro. In addition, osteogenic effect was examined in a rabbit model of femoral defect. The results revealed that addition of collagen/calcitonin did not substantially alter physical properties and degradation rate of bone cement specimens. Calcitonin was released into culture medium in a two-phase manner. Osteogenic effect of conditioned medium derived from calcitonin containing bone cement was observed. Finally, de novo bone growth and bone mineralization across the bone defect area were observed in rabbits after implantation of composite bone cement specimens. In conclusion, this novel calcitonin-loaded composite calcium phosphate bone cement exhibits biocompatibility, bioresorbability, osteoinductivity, and osteoconductivity, which may be suitable for clinical use.
EgolKANauthALeeM, et al.
Bone grafting: sourcing, timing, strategies, and alternatives. J Orthop Trauma2015;
29(Suppl 12): S10–14.
2.
MauffreyCHakeMEChadayammuriV, et al.
Reconstruction of long bone infections using the induced membrane technique: tips and tricks. J Orthop Trauma2016;
30: e188–e193.
3.
WieseAPapeHC.Bone defects caused by high-energy injuries, bone loss, infected nonunions, and nonunions. Orthop Clin North Am2010;
41: 1–4.
4.
CampanaVMilanoGPaganoE, et al.
Bone substitutes in orthopaedic surgery: from basic science to clinical practice. J Mater Sci Mater Med2014;
25: 2445–2461.
5.
LaurencinCKhanYEl-AminSF.Bone graft substitutes. Expert Rev Med Dev2006;
3: 49–57.
6.
SohnHSOhJK.Review of bone graft and bone substitutes with an emphasis on fracture surgeries. Biomater Res2019;
23: 9.
7.
FengX.Chemical and biochemical basis of cell-bone matrix interaction in health and disease. Curr Chem Biol2009;
3: 189–196.
8.
GhassemiTShahroodiAEbrahimzadehMH, et al.
Current concepts in scaffolding for bone tissue engineering. Arch Bone Jt Surg2018;
6: 90–99.
9.
MurshedM.Mechanism of bone mineralization. Cold Spring Harb Perspect Med2018;
8: a031229.
10.
GulinelliJLQueirozTPHochuli-VieiraE, et al.
Use of calcium phosphate cement for repairing bone defects: histomorphometric and immunohistochemical analyses. J Craniofac Surg2019;
30: 1016–1021.
11.
LewickiKPrioreschiBKoenigK, et al.
The effect of absorbable calcium sulfate on wear rates in ultra-high-Molecular-weight polyethylene: potential implications for its use in treating arthroplasty infections. J Am Acad Orthop Surg2017;
25: e114–e120.
12.
CivininiRCaponeACarulliC, et al.
The kinetics of remodeling of a calcium sulfate/calcium phosphate bioceramic. J Mater Sci Mater Med2017;
28: 137.
13.
BhuiyanDBMiddletonJCTannenbaumR, et al.
Bone regeneration from human mesenchymal stem cells on porous hydroxyapatite-PLGA-collagen bioactive polymer scaffolds. Biomed Mater Eng2017;
28: 671–685.
14.
HuMHLeePYChenWC, et al.
Incorporation of collagen in calcium phosphate cements for controlling osseointegration. Materials2017;
10: 910.
15.
PalmerINelsonJSchattonW, et al.
Biocompatibility of calcium phosphate bone cement with optimised mechanical properties: an in vivo study. J Mater Sci Mater Med2016;
27: 191. .
16.
SolheimE.Growth factors in bone. Int Orthop1998;
22: 410–416.
17.
YunYRJangJHJeonE, et al.
Administration of growth factors for bone regeneration. Regen Med2012;
7: 369–385.
18.
LeeGHMakkarPPaulK, et al.
Incorporation of BMP-2 loaded collagen conjugated BCP granules in calcium phosphate cement based injectable bone substitutes for improved bone regeneration. Mater Sci Eng C Mater Biol Appl2017;
77: 713–724.
19.
MatsuseKHashimotoYKakinokiS, et al.
Periodontal regeneration induced by porous alpha-tricalcium phosphate with immobilized basic fibroblast growth factor in a canine model of 2-wall periodontal defects. Med Mol Morphol2018;
51: 48–56.
20.
SchumacherMReitherLThomasJ, et al.
Calcium phosphate bone cement/mesoporous bioactive glass composites for controlled growth factor delivery. Biomater Sci2017;
5: 578–588.
21.
CoteGJGrubbsEGHofmannMC.Thyroid C-cell biology and oncogenic transformation. Recent Results Cancer Res2015;
204: 1–39.
22.
BandeiraLLewieckiEMBilezikianJP.Pharmacodynamics and pharmacokinetics of oral salmon calcitonin in the treatment of osteoporosis. Expert Opin Drug Metab Toxicol2016;
12: 681–689.
23.
MorabitoCD'AlimonteIPierdomenicoL, et al.
Calcitonin-induced effects on amniotic fluid-derived mesenchymal stem cells. Cell Physiol Biochem2015;
36: 259–273.
24.
GouYTianFKongQ, et al.
Salmon calcitonin attenuates degenerative changes in cartilage and subchondral bone in lumbar facet joint in an experimental rat model. Med Sci Monit2018;
24: 2849–2857.
25.
LiDXFanHSZhuXD, et al.
Controllable release of salmon-calcitonin in injectable calcium phosphate cement modified by chitosan oligosaccharide and collagen polypeptide. J Mater Sci Mater Med2007;
18: 2225–2231.
26.
ASTM C266-08. Standard test method for time of setting of hydraulic-cement paste by gillmore needles.
West Conshohocken, PA:
ASTM International, 2008.
27.
QuGXYingZMZhaoCC, et al.
Mechanical properties and porosity of acrylic cement bone loaded with alendronate powder. Int J Med Sci2018;
15: 1458–1465.
28.
WuKChenYCHsuYM, et al.
Enhancing drug release from antibiotic-loaded bone cement using porogens. J Am Acad Orthop Surg2016;
24: 188–195.
29.
BoaniniEGazzanoMNerviC, et al.
Strontium and zinc substitution in beta-tricalcium phosphate: an X-ray diffraction, solid state NMR and ATR-FTIR study. JFB2019;
10: 20.
30.
DashSMurthyPNNathL, et al.
Kinetic modeling on drug release from controlled drug delivery systems. Acta Pol Pharm2010;
67: 217–223.
31.
O'ConnellKPierlotCO'SheaH, et al.
Host responses to a strontium releasing high boron glass using a rabbit bilateral femoral defect model. J Biomed Mater Res B Appl Biomater2017;
105: 1818–1827.
32.
van GaalenSMKruytMCGeuzeRE, et al.
Use of fluorochrome labels in in vivo bone tissue engineering research. Tissue Eng Part B Rev2010;
16: 209–217.
33.
ZhangYGYangZZhangH, et al.
Negative pressure technology enhances bone regeneration in rabbit skull defects. BMC Musculoskelet Disord2013;
14: 76.
34.
AtkinsGJFindlayDMAndersonPH, et al. Chapter 23 – target genes: bone proteins. In: DFeldmanJWPikeJSAdams (eds) Vitamin D. 3rd ed.San Diego:
Academic Press, 2011, pp.411–424.
35.
MistrySRoySMaitraNJ, et al.
A novel, multi-barrier, drug eluting calcium sulfate/biphasic calcium phosphate biodegradable composite bone cement for treatment of experimental MRSA osteomyelitis in rabbit model. J Control Release2016;
239: 169–181.
36.
BoyleKKSosaBOsagieL, et al.
Vancomycin-laden calcium phosphate-calcium sulfate composite allows bone formation in a rat infection model. PLoS One2019;
14: e0222034.
37.
ChocholataPKuldaVBabuskaV.Fabrication of scaffolds for bone-tissue regeneration. Materials2019;
12: 568.
38.
RyanEJRyanAJGonzalez-VazquezA, et al.
Collagen scaffolds functionalised with copper-eluting bioactive glass reduce infection and enhance osteogenesis and angiogenesis both in vitro and in vivo. Biomaterials2019;
197: 405–416.
39.
Florencio-SilvaRSassoGRSasso-CerriE, et al.
Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed Res Int2015;
2015: 421746.
40.
KellerJCatala-LehnenPHuebnerAK, et al.
Calcitonin controls bone formation by inhibiting the release of sphingosine 1-phosphate from osteoclasts. Nat Commun2014;
5: 5215.
41.
GooiJHChiaLYWalshNC, et al.
Decline in calcitonin receptor expression in osteocytes with age. J Endocrinol2014;
221: 181–191.
42.
FarleyJDimaiHPStilt-CoffingB, et al.
Calcitonin increases the concentration of insulin-like growth factors in serum-free cultures of human osteoblast-line cells. Calcif Tissue Int2000;
67: 247–254.
43.
TellaSHGallagherJC.Prevention and treatment of postmenopausal osteoporosis. J Steroid Biochem Mol Biol2014;
142: 155–170.
44.
Halling LinderCEk-RylanderBKrumpelM, et al.
Bone alkaline phosphatase and tartrate-resistant acid phosphatase: potential co-regulators of bone mineralization. Calcif Tissue Int2017;
101: 92–101.
